Correlation between postprandial bile acids and body fat mass in healthy normal-weight subjects.

BACKGROUND: Bile acids (BAs) play important roles in glucose regulation and energy homeostasis via G protein-coupled receptors, such as enteroendocrine L cell TGR5. The aim of the present study was to investigate the relationship between postprandial BA levels and body composition after ingestion of a standard test meal. METHODS: Eleven healthy subjects of normal weight (body-mass index, 22.0 ± 1.6 kg/m(2) [mean ± SD]), ingested a 400-kcal test meal, and blood samples were obtained from them before ingestion and every 30 min for 120 min after ingestion. The BA fractions were measured with high-performance liquid chromatography. To evaluate body composition, body impedance analysis was performed 1h before ingestion of the test meal. RESULTS: Concentrations of both total BA and total glycine-conjugated BA (GCBA) at 30, 60, 90, and 120 min after test-meal ingestion were significantly higher than those at baseline. The body-mass index was correlated with total GCBA at baseline. Moreover, body fat mass was correlated with total GCBA at 30 min (r=-0.688, P=0.019) and 60 min (r=-0.642, P=0.033) and with total BA at 30 min (r=-0.688, P=0.019) and 60 min (r=-0.642, P=0.033). CONCLUSION: The postprandial BA response is inversely related with body fat mass in healthy subjects of normal weight.

Change in urinary N-acetyl-ß-d-glucosaminidase levels relevant to postprandial glycemic control conditions in subjects without diabetes mellitus.

BACKGROUND: To assess the relationship between the serum level of 1,5-anhydroglucitol (1,5-AG), a marker of postprandial hyperglycemia, and the ratio of the urinary activity of N-acetyl-ß-d-glucosaminidase to creatinine (NAG index) in subjects without diabetes mellitus (DM). METHODS: This was a cross-sectional study with 495 subjects without DM who had an estimated glomerular filtration rate≥30ml/min/1.73m(2). Subjects were divided into tertiles based on serum 1,5-AG levels: high (>21.0µg/ml), middle (14.0-21.0µg/ml), and low (<14.0µg/ml). Adjusted odds ratios for an elevated urinary NAG index (>5.8U/g creatinine) according to the HbA1c (≤5.4%, 5.5%-5.9%, and 6.0%-6.4%) and 1,5-AG tertiles were calculated. RESULTS: The NAG index was negatively correlated with the serum 1,5-AG level in all subjects. The slopes of the regression lines for these variables did not differ significantly between elderly (≥65y) and nonelderly subjects. As compared with high 1,5-AG and HbA1c≤5.4%, the odds ratios for an elevated urinary NAG index increased progressively to 7.71 across the categories of low 1,5-AG and HbA1c of 6.0% to 6.4%. CONCLUSION: Poor control of postprandial glucose is related to an elevated urinary NAG index in persons without DM.

What characteristics at baseline are associated with the glucose-lowering effect of colestimide in patients with type 2 diabetes and hypercholesterolemia according to response to treatment?

Colestimide, an anion exchange resin, reportedly improves glycemic control in patients with type 2 diabetes. However, no studies of the glucose-lowering effect of colestimide have identified responders and nonresponders. In the present study, we compared glycemic control, lipids, and body-mass index (BMI) among patients with type 2 diabetes receiving colestimide (n=59) until 24 weeks after the start of treatment. Subjects were classified as responders to treatment (n=40), who showed a 15% or greater decrease in glycated hemoglobin (HbA1c) or a 20% or greater decrease in plasma glucose level or both after 24 weeks of colestimide treatment as compared with baseline; nonresponders showed HbA1c>11.5% or fasting plasma glucose (FPG)>250 mg/dL during the course of the study and <15% decrease in HbA1c levels or <20% decrease in FPG levels or both after 24 weeks of colestimide treatment as compared with baseline. In responders, FPG decreased significantly from 196 ± 91 mg/dL to 125 ± 47 mg/dL after 24 weeks (P<0.001), and HbA1c decreased from 9.1% ± 2.0% to 7.0% ± 0.9% (P<0.001). In nonresponders, HbA1c decreased significantly from 7.7% ± 2.9% to 7.6% ± 1.2% (P<0.05). Multiple logistic regression analysis revealed that baseline HbA1c and the presence of cholelithiasis were significant determinants of the response to colestimide treatment when corrected for sex, age, triglyceride levels, and BMI at baseline and the presence of fatty liver. In conclusion, baseline HbA1c and the presence of cholelithiasis have strong and independent influences on the glucose-lowering effect of colestimide.

Serum uric acid in relation to serum 1,5-anhydroglucitol levels in patients with and without type 2 diabetes mellitus.

OBJECTIVES: The aim of this study was to examine the relationship between serum levels of uric acid (UA) and 1,5-anhydroglucitol (1,5-AG) in elderly subjects (60 years or older; mean age, 73.0±7.2 years) with and without type 2 diabetes mellitus (DM). METHODS: Subjects with DM (n=97) and without DM (n=360) were recruited from among our outpatients (estimated glomerular filtration rate≥45 mL min⁻¹ 1.73 m⁻², and urine protein equivalent to <1.0 g/L), and a cross-sectional study was performed with simple linear regression and stepwise multiple linear regression analyses. RESULTS: The mean serum UA levels of men were significantly higher than those of women in both groups. The mean serum 1,5-AG levels of men were significantly higher than those of women in the non-DM group. There were positive correlations (indicated by Pearson's correlation coefficients) between serum UA levels and 1,5-anhydroglucitol levels in all patients and in both men and women. Simple linear regression and multiple linear regression analyses showed that the serum 1,5-AG levels were significantly and positively correlated with the serum UA level in both the non-DM group and the DM group. In the non-DM group, HbA1c levels, as well as 1,5-AG levels, were positively correlated with serum UA levels. Furthermore, the correlation between 1,5-AG and UA levels was stronger in subjects with DM than in subjects without DM. CONCLUSIONS: These results suggest that the serum 1,5-AG level is an independent factor associated with serum UA levels in the nondiabetic state, as in DM.

Low-molecular-weight lipoprotein (a) and low relative lymphocyte concentration are significant and independent risk factors for coronary heart disease in patients with type 2 diabetes mellitus: Lp(a) phenotype, lymphocyte, and coronary heart disease.

BACKGROUND: The aim of the present prospective study was to examine whether lipoprotein (a) [Lp(a)] phenotypes and/or low relative lymphocyte concentration (LRLC) are independently associated with coronary heart disease (CHD) in patients with type 2 diabetes mellitus (T2DM). METHODS: Serum Lp(a) concentration, Lp(a) phenotypes, and RLC were analyzed in 214 subjects. Lp(a) phenotypes were classified into 7 subtypes according to sodium dodecyl sulfate-agarose gel electrophoresis by Western blotting. Subjects were assigned to the low-molecular-weight (LMW (number of KIV repeats: 11-22) ) and high-molecular-weight (HMW( number of KIV repeats: >22 )) Lp(a) groups according to Lp(a) phenotype and to the LRLC (RLC: <20.3%) and normal RLC (NRLC; RLC: ≥20.3%) groups according to RLC. A CHD event was defined as the occurrence of angina pectoris or myocardial infarction during the follow-up period. RESULTS: During the follow-up period, 30 cases of CHD events were verified. Neutrophil count showed no correlation with CHD, while relative neutrophil concentration and RLC showed positive and negative correlations, respectively, with CHD. The Cox proportional hazard model analysis revealed the following hazard ratios adjusted for LMW Lp(a), LRLC, and LMW Lp(a) + LRLC: (4.31; 95% confidence interval [CI], 1.99-9.32; P < 0.01, 3.621; 95% CI, 1.50-8.75; P < 0.05, and 7.15; 95% CI, 2.17-23.56; P < 0.01, respectively). CONCLUSIONS: Our results suggest that both LMW Lp(a) and LRLC are significant and independent risk factors for CHD and that the combination thereof more strongly predicts CHD in patients with T2DM.

Urinary N-acetyl-ß-D-glucosaminidase levels are positively correlated with 2-hr plasma glucose levels during oral glucose tolerance testing in prediabetes.

BACKGROUND: Urinary N-acetyl-ß-D-glucosaminidase (NAG) excretion is increased in patients with impaired glucose tolerance (IGT). This study investigated when during the oral glucose tolerance test (OGTT) the plasma glucose, urine glucose, and insulin levels correlate most strongly with urinary N-acetyl-ß-d-glucosaminidase (NAG) levels in prediabetic subjects. METHODS: The OGTT was administered to 80 subjects who had not yet received a diagnosis of diabetes mellitus (DM) and in whom HbA1c levels were ≤6.8% and fasting plasma glucose levels were <7.0 mmol/l. Forty-two subjects had normal glucose tolerance (NGT), 31 had impaired glucose tolerance (IGT), and 7 had DM according to World Health Organization criteria. Serum levels of cystatin C, the estimated glomerular filtration rate, the urinary albumin-to-creatinine (Cr) ratio, urinary and serum ß2-microglobulin, and urinary NAG were measured as markers of renal function. RESULTS: NAG levels were significantly higher in subjects with DM and in subjects with IGT than in subjects with NGT. No significant associations were observed between glycemic status and other markers of renal function. Multiple linear regression analysis showed that the NAG level was positively correlated with plasma glucose levels at 120 min of the OGTT and was associated with the glycemic status of prediabetic patients. CONCLUSION: These results suggest that postprandial hyperglycemia is an independent factor that causes renal tubular damage in prediabetes patients.

The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance.

BACKGROUND: Previous studies have demonstrated that postprandial hyperglycemia attenuates brachial artery flow-mediated dilation (FMD) in prediabetic patients, in diabetic patients, and even in normal subjects. We have previously reported that postprandial hyperinsulinemia also attenuates FMD. In the present study we evaluated the relationship between different degrees of postprandial attenuation of FMD induced by postprandial hyperglycemia and hyperinsulinemia and differences in ingested carbohydrate content in non-diabetic individuals. METHODS: Thirty-seven healthy subjects with no family history of diabetes were divided into 3 groups: a 75-g oral glucose loading group (OG group) (n = 14), a test meal group (TM group) (n = 12; 400 kcal, carbohydrate content 40.7 g), and a control group (n = 11). The FMD was measured at preload (FMD0) and at 60 minutes (FMD60) and 120 (FMD120) minutes after loading. Plasma glucose (PG) and immunoreactive insulin (IRI) levels were determined at preload (PG0, IRI0) and at 30 (PG30, IRI30), 60 (PG60, IRI60), and 120 (PG120, IRI120) minutes after loading. RESULT: Percentage decreases from FMD0 to FMD60 were significantly greater in the TM group (-21.19% ± 17.90%; P < 0.001) and the OG group (-17.59% ± 26.64%) than in the control group (6.46% ± 9.17%; P < 0.01), whereas no significant difference was observed between the TM and OG groups. In contrast, the percentage decrease from FMD0 to FMD120 was significantly greater in the OG group (-18.91% ± 16.58%) than in the control group (6.78% ± 11.43%; P < 0.001) or the TM group (5.22% ± 37.22%; P < 0.05), but no significant difference was observed between the control and TM groups. The FMD60 was significantly correlated with HOMA-IR (r = -0.389; P < 0.05). In contrast, FMD120 was significantly correlated with IRI60 (r = -0.462; P < 0.05) and the AUC of IRI (r = -0.468; P < 0.05). Furthermore, the percentage change from FMD0 to FMD120 was significantly correlated with the CV of PG (r = 0.404; P < 0.05), IRI60 (r = 0.401; p < 0.05) and the AUC of IRI (r = 0.427; P < 0.05). No significant correlation was observed between any other FMDs and glucose metabolic variables. CONCLUSION: Differences in the attenuation of postprandial FMD induced by different postprandial insulin levels may occur a long time postprandially but not shortly after a meal.

Correlation between asymptomatic leukocyturia and urinary N-acetyl-ß-d-glucosaminidase in women.

Urinary N-acetyl-ß-d-glucosaminidase (NAG) has been suggested as a marker for early diabetic nephropathy. This study aimed to prospectively investigate the relationship between asymptomatic leukocyturia (ASL) and NAG in women. One hundred and five female outpatients aged 31-86 years were selected for a 10-year follow-up study. We regarded ASL to be present if two consecutive samples were found to have 10 or more leukocytes/high-power field at 400× magnifications in a centrifuged midstream urine sample both at baseline and 10 years later. The urinary activities of NAG to creatinine ratios (NAG index) were measured in random spot urine samples. Patients without ASL at the beginning of the study were followed. The patients with ASL had diabetes mellitus more frequently than those without ASL at baseline and after 10 years. Residual urine volume and the NAG index were significantly higher in the former than in the latter (p = 0.014 and p = 0.002, respectively) at baseline. During the observation period, 15 patients had ASL (30.6%). Although a gradual increase in the NAG index was found during the study in both patients who had ASL and those who did not, the mean NAG index was significantly higher in the latter during study period (6.4 ± 3.0 vs. 9.8 ± 5.5, p = 0.004, 9.4 ± 5.2 vs. 11.5 ± 6.4, p = 0.328, respectively). On multiple logistic regression analysis, the NAG index at the beginning of the study was an independent predictor of ASL. These results demonstrate that the NAG index may serve as an indicator of ASL in women.

Effects of bile-acid-binding resin (colestimide) on blood glucose and visceral fat in Japanese patients with type 2 diabetes mellitus and hypercholesterolemia: an open-label, randomized, case-control, crossover study.

OBJECTIVE: The objective was to examine the effects of colestimide on blood glucose, visceral fat, adipocytokines, and bile acid conjugate fractions in Japanese patients. METHODS: This study was an open-label, randomized, case-control, crossover study of colestimide 3 g/day in 40 Japanese patients with type 2 diabetes mellitus (T2D) and hypercholesterolemia. Patients were assigned to the colestimide group in which pravastatin and colestimide were administered orally and to the statin group in which pravastatin alone was administered orally. The principal outcome measures were serum lipid levels, fasting plasma glucose level in the early morning, hemoglobin A1c (HbA(1c)), visceral fat area (VFA), and serum 1,5-anhydroglucitol (1,5-AG) level. RESULTS: Serum low-density lipoprotein cholesterol levels significantly decreased from 113±38 mg/dl at baseline to 90±20 mg/dl (P=.009) at week 12 of colestimide administration. HbA(1c) significantly decreased from 7.4%±0.9% at baseline to 6.9%±0.9% (P=.001) at week 12 of colestimide administration. Serum 1,5-AG levels increased from 9.4±10.1 µg/ml to 12.4±9.5 µg/ml (P=.05) at week 12 of colestimide administration. The statin group showed no significant changes in lipids and 1,5-AG. However, ΔVFA was inversely correlated with Δcholic acid, and multivariate analysis revealed that ΔVFA was a significant explanatory variable. CONCLUSIONS: Colestimide holds promise not only for the treatment of hypercholesterolemia but also for the possible improvement of T2D and visceral fat obesity.

[A case of ileus caused by a fecalith in an elderly patient with severe dementia].

An 82-year-old woman with severe dementia, living in a nursing home, had severe chronic constipation, possibly due to the presence of multiple risk factors for constipation such as a past history of abdominal open surgery, diabetes, hypothyroidism, and bedridden status. She visited our department accompanied by nursing staff with complaints of nausea and vomiting. Abdominal X-ray films and computed tomography (CT) images showed ileus. We diagnosed strangulation ileus, and performed an emergency laparotomy. There was a mobile cystic lesion located 180 cm from the ileocecal junction which was causing the intestinal obstruction. The cystic lesion was surgically removed via an enterotomy. The greatest dimensions of the cystic lesion were 5 × 3 cm, and it was histologically diagnosed as a fecalith. We report a rare case of ileus caused by a fecalith in an elderly patient.

Glucose levels during oral glucose tolerance tests and gamma-glutamyl transpeptidase are predictors of change from normal to impaired glucose tolerance in healthy middle-aged Japanese men.

We evaluated the predictors of the development from normal to impaired glucose tolerance (IGT) in healthy middle-aged Japanese men. Forty male subjects who showed normal glucose tolerance (NGT) levels based on WHO criteria and who had undergone 75-g OGTT annually for 10 years were selected in the database of medical checkups retrospectively, and divided into two groups: those retaining NGT and those that developed IGT. Gamma-glutamyl transpeptidase (GGT) and the glucose levels at 30 and 60 min were significantly associated with the development of IGT in the Cox proportional hazard model. However, other clinical characteristics and the glucose levels at pre-load and at 120 min were not significantly associated with the development of IGT. GGT and the glucose levels at 30 and 60 min after the 75-g glucose load were predictors of development from NGT to IGT in healthy middle-aged Japanese men.

Asymptomatic leukocyturia and the autonomic nervous system in women.

BACKGROUND: The present study sought to investigate the relationship between asymptomatic leukocyturia (ASL) and autonomic nervous function by power spectral analysis of the R-R intervals in women. METHODS: One hundred and forty-two female outpatients aged 23-91 years were studied. We regarded ASL to be present if two consecutive samples were found to have 10 or more leukocytes/high-power field at x400 magnification in a centrifuged midstream urine sample. The R-R intervals of all subjects were measured by the wavelet transform analysis system. This system detected R-R variation data distributed in two bands: low-frequency power (LF) (0.04-0.15 Hz) and high-frequency power (HF) (0.15-0.40 Hz). The ratio of LF to HF (LF/HF) was also determined. Post-void residual urine volume was measured using an automated, compact 3-D ultrasound device. RESULTS: The patients with ASL had diabetes mellitus more frequently than those without ASL. Residual urine volume was significantly higher in the former than in the latter, while the HF values in both a recumbent position and a standing position were significantly lower in the former than in the latter (P = 0.003, P = 0.001, respectively). However, there were no significant differences in LF or LF/HF values in either a recumbent or a standing position between the two groups. The HF values in both a recumbent position and in a standing position were independent indicators of ASL, even after adjustment for age, diabetes mellitus and residual urine volume. CONCLUSION: The present study reveals the relationship between ASL and impairment of the parasympathetic nervous system in women.

Colestimide lowers plasma glucose levels and increases plasma glucagon-like PEPTIDE-1 (7-36) levels in patients with type 2 diabetes mellitus complicated by hypercholesterolemia.

BACKGROUND: Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes complicated by hypercholesterolemia. AIM: To examine the mechanism by which colestimide decreases plasma glucose levels in the above patients. METHODS: A total of 16 inpatients with type 2 diabetes complicated by hypercholesterolemia received colestimide for 1 week after their plasma glucose levels stabilized. We measured plasma glucose, serum immunoreactive insulin (IRI), serum lipid, plasma glucagon, and plasma glucagon-like peptide-1 (GLP-1) levels. These variables at baseline and 1 week of colestimide administration were compared. RESULTS: Preprandial plasma glucose levels (baseline: 132 +/- 33 mg/dL vs. completion: 118 +/- 43 mg/dL, P=0.073) tended to decrease after colestimide administration, while 1-hr postprandial plasma glucose levels (baseline: 208 +/- 49 mg/dL vs. completion: 166 +/- 30 mg/dL, P<0.001) and 2-hr postprandial plasma glucose levels (baseline: 209 +/- 56 mg/dL vs. completion: 178 +/- 39 mg/dL, P=0.015) decreased significantly at 1 week of colestimide administration. The 2-hr postprandial plasma GLP-1 level was significantly (P=0.015) higher at 1 week of colestimide administration as compared with the baseline level, while there were no significant changes in preprandial and 1-hr postprandial plasma GLP-1 levels. CONCLUSIONS: The GLP-1-increasing activity of colestimide may explain, at least in part, the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes complicated by hypercholesterolemia.

Blood glucose-lowering activity of colestimide in patients with type 2 diabetes and hypercholesterolemia: a case-control study comparing colestimide with acarbose.

BACKGROUND: An anion exchange resin has been reported to lower blood glucose levels in patients with type 2 diabetes. AIM: To examine, in comparison with an alpha-glucosidase inhibitor, the usefulness of colestimide in lowering blood glucose levels in patients with type 2 diabetes and hypercholesterolemia. METHODS: Thirty-three patients with type 2 diabetes and hypercholesterolemia were more or less randomly assigned to receive either colestimide (17 patients) or acarbose (16 patients). At 10 time points before and after administration, plasma glucose levels and serum lipid concentrations were measured in all subjects, and the J-index and M-value were calculated. RESULTS: Patients receiving colestimide showed significant decreases in glucose levels 2 hours after breakfast (from 216.9 +/- 37.2 mg/dl before treatment to 191.1 +/- 40.9 mg/dl after treatment; p=0.008), in the J-index (from 42.6 +/- 14.5 to 32.6 +/- 9.8; p<0.001), and in the M-value (from 23.1 +/- 12.1 to 14.6 +/- 7.1; p<0.001). CONCLUSION: In patients with type 2 diabetes and hyperlipidemia, colestimide was suggested to have blood glucose-lowering activity as does acarbose.

[Epidemiology of elderly diabetes mellitus in Japan].

Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and post challenge hyperglycemia in the older population. Diabetes in the elderly is not a single entity, but a heterogeneous group of conditions. A further 9% may have undetected/asymptomatic hyperglycemia. Several studies have also shown that fasting blood glucose rises with age (about 1-2 mg/dl/decade) and postprandial glucose by about 15 mg/dl/decade, leading to a mild glucose intolerance. Age-related glucose intolerance in humans is often accompanied by insulin resistance. The relative contribution of decreased insulin secretion vs. increased insulin resistance to the pathogenesis of type 2 diabetes mellitus has been the subject of long-standing controversy.